Project Summary Nearly half of the US adult population are type 2 diabetic (T2D) or pre-diabetic, and there is increasing evidence of a link between T2D and depression, particularly the core clinical feature of anhedonia. A known mechanistic overlap between T2D and major depression is increased inflammatory activity. In the case of T2D, a key role has been established for advanced glycation end products (AGEs) and their receptor (RAGE) in pro-inflammatory gene activation and insulin resistance. AGEs form endogenously, but also originate exogenously, with dietary sugar and high fat foods being rich sources. We have previously observed that a high fat, high sugar diet decreases evoked dopamine (DA) release in nucleus accumbens (NAc) and induces NAc insulin receptor (InsR) subsensitivity. Although RAGE is expressed in brain, there has been very little investigation of diet effects on brain RAGE expression, and almost nothing is known about brain RAGE effects on CNS function and behavior. New preliminary data indicate that the high fat, high sugar diet, found previously to diminish DA and InsR function, increases expression of RAGE and its key intracellular signaling effector molecule, DIAPH1 in NAc but not caudate putamen. We propose to investigate whether diet-induced RAGE expression and signaling in the NAc induce behavioral signs of anhedonia in rats. We predict that a high-fat, high-sugar diet elevates circulating levels of AGEs, increases expression of RAGE and DIAPH1 in the NAc, and induces behavioral signs of anhedonia in brain stimulation reward and conditioned place preference assays. To assess the causal connection between brain RAGE and behavioral changes, a recently available small-molecule high-affinity RAGE inhibitor will be continuously infused into the brain ventricular system. Our findings might identify a mechanistic basis for the link between T2D and depression and, perhaps, diet-induced anhedonic effects that drive escalating consumption of energy-dense palatable food aimed at achieving reward homeostasis.